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The Journal of Neuroscience, June 29, 2005, 25(26):6057-6065; doi:10.1523/JNEUROSCI.0454-05.2005

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Cellular/Molecular
Interplay between Na⁺/Ca²+ Exchangers and Mitochondria in Ca²+ Clearance at the Calyx of Held

Myoung-Hwan Kim,¹ Natalya Korogod,² Ralf Schneggenburger,² Won-Kyung Ho,¹ and Suk-Ho Lee¹

¹National Research Laboratory for Cell Physiology, Department of Physiology, Seoul National University College of Medicine, Chongno-Ku, Seoul 110-799, Korea, and ²Arbeitsgruppe Synaptische Dynamik und Modulation and Abteilung Membranbiophysik, Max-Planck-Institut für Biophysikalische Chemie, D-37077 Göttingen, Germany

The clearance of Ca²⁺ from nerve terminals is critical for determining the build-up of residual Ca²⁺ after repetitive presynaptic activity. We found previously that K⁺-dependent Na⁺/Ca²⁺ exchangers (NCKXs) show polarized distributions in axon terminals of supraoptic magnocellular neurons and play a major role in Ca²⁺ clearance. The role of NCKXs in presynaptic terminals, however, has not been studied. We investigated the contribution of NCKX in conjunction with other Ca²⁺ clearance mechanisms at the calyx of Held by analyzing the decay of Ca²⁺ transients evoked by depolarizing pulses. Inhibition of Na⁺/Ca²⁺ exchange by replacing external Na⁺ with Li⁺ decreased the Ca²⁺ decay rate by 68%. Selective inhibition of NCKX by replacing internal K⁺ with TEA⁺ (tetraethylammonium) or Li⁺ decreased the Ca²⁺ decay rate by 42%, and the additional inhibition of the K⁺-independent form of Na⁺/Ca²⁺ exchanger (NCX) by reducing external [Na⁺] caused an additional decrease by 26%. Inhibition of plasma membrane Ca²⁺-ATPase (PMCA) decreased the Ca²⁺ decay rate by 23%, whereas inhibition of SERCA (smooth endoplasmic reticulum Ca²⁺-ATPase) had no effect. The contribution of mitochondria was negligible for small Ca²⁺ transients but became apparent at [Ca²⁺]_i > 2.5 µM, when Na⁺/Ca²⁺ exchange became saturated. Mitochondrial contribution was also observed when the duration of Ca²⁺ transients was prolonged by inhibiting Na⁺/Ca²⁺ exchangers or by increasing Ca²⁺ buffers. These results suggest that, in response to small Ca²⁺ transients (<2 µM), Ca²⁺ loads are cleared from the calyx of Held by NCKX (42%), NCX (26%), and PMCA (23%), and that mitochondria participate when the Ca²⁺ load is larger or prolonged.

Key words: presynaptic; calcium clearance; NCX; NCKX; mitochondria; calyx of Held

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Received Feb 2, 2005; revised May 13, 2005; accepted May 14, 2005.

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